Sunday, May 20, 2012

Two more heavily publicized papers came out in the past week or so, just in time to be fodder for questions at my talk on Evolutionary Psychiatry and Alzheimer's Dementia in the upcoming week.

Have you ever heard the Adagio from Spartacus? Hang in there for a little bit. Around 1:09 you get the early rendition of one of the more romantic themes in classical music, repeated with greater power later in the ballet (2:47 and 7:04). The Russian composers really knew how to sock it to you with a good theme.

Can we say the same of rat researchers from UCLA? Well, excepting our own good friend and AHS president Aaron Blaisdell, the jury is still out… These researchers pulled out some interesting things, though, in their little study on 24 rats.

This paper combines everything awesome and evil all at once. Rat study. Fructose! DHA. Mazes. The authors even begin the paper not with an abstract but with highlighted Key Points: We provide novel evidence for the effects of metabolic dysfunctions on brain function using the rat model of metabolic syndrome induced by high fructose intake. Etc.

So… we have some rats. There are two diets and two drinks. Group 1 gets regular rat chow with omega 3 and water to drink. Group 2 gets regular rat chow with omega 3 and a 15% fructose drink instead of water. Group 3 gets water and omega 3 deficient diets (and I doubt it is so easy to make a human in the wild quite so omega3 deficient as these rats), and group 4 gets the double whammy of an omega 3 deficient diet and the 15% fructose solution. The diets go for 6 weeks, and in that time, we have a pretty remarkable change in the fructose-slurping rates.

The fructosed rats drink a lot more than the plain water-drinking rats, and even though they eat less food than the plain water rats, they take in more calories. By the end of the 6 weeks, the fructosed rats have high glucose and insulin levels, and the triglyceride levels of poor group 4 (given fructose and omega 3 deficient diet) are over twice the levels of group 1 (omega 3 food + water). The researchers found that the omega 3 in the diet seemed to protect the group 2 rats a little from the fructose, with less weight gain and less rat metabolic syndrome.

These rats had also been trained to go through a maze, and the fructose-poisoned omega 3 depleted rats did worse than any of the other groups in remembering how to get through the maze. They lost the maze race, big time. Again, the rats who had fructose and omega 3 had relatively preserved maze-solving abilities.

The researchers measured very specific elements in the rats' bodies and brains after the experiment. Measures of energy metabolism were decreased in poor group 4, whereas omega 3 seemed to increase energy metabolism. Other chemicals known to be important in the ability of the nerves to adapt and change according to different stimuli (called synaptic plasticity) were very decreased in the omega 3 deficient rats, and very much decreased in the fructose-poisoned omega 3 deficient rats. Group 2 rats (+ omega 3, + fructose) had, again, some protection from the bad effects of the fructose.

And, not surprisingly, the omega 3 deficient rats had a decreased amount of DHA in the brain and an increased amount of omega 6 fats and their metabolites, like arachidonic acid.

So, we've now proven that fructose is bad (in the context of an excess calorie diet), and omega 3 is protective, and the main point is to not deprive your rats of omega 3.

Sugar can indeed make you dumb (in the context of an excess calorie diet). Eating lab rat chow completely devoid of omega 3 can make you even dumber. I don't recommend it. But you can see how a modern processed food diet can mimic these changes. Soda or juice or red bull or sweetened beverage of your choice and a lack of omega 3 does not a happy liver or brain make, and the changes occur quickly.

And now the second diet and dementia study of the week (involving actual humans! However, it is another observational study from the hospital where I'm academically attached). Participants in the Women's Health Study (about 39,000 female health care professionals) filled out a food frequency questionnaire at baseline, and beginning five years later, an older sub cohort (about 6000 women over 65) underwent serial cognitive testing via telephone over the course of an additional four years. Data was gathered and statisticians went to work.

The women underwent cognitive testing three times, with the time between the 1st and 3rd test being an average of 4 years. Women tended to do better the second time than the first time (having learned what the tests were going to be), but at the end of the four years, the scores dropped for most women from the second to the third test. It declined the most for women who ate the most saturated fat, and actually test scores continued to improve for women who consumed the most monounsaturated fat.

There were no associations between total fat, trans fat, and polyunsaturated fat (which is mostly omega 6) and cognitive change.

By the time you pull out covarites you have a mell of a hess. Saturated fat intake was associated with lower rates of high cholesterol, by the way (statinization?? This part of the study occurred from 1998-2002. Statins came out in the late 80s and lipitor, the biggest-selling one I believe, was released in 1998. Though it is hard to tell if women on statins would have automatically been put into the "hypercholesterolemia" group or if just total cholesterol was used to make this group. There are many frustrating things about the way the data is presented in this study). MUFA (olive oil) consumption was also correlated with lower total cholesterol. Women with known cardiovascular disease (history of a myocardial infarction, stroke, coronary artery bypass or stenting) were taken out of the data and the trend remained similar. More total fat intake was associated with lower exercise, smoking, and higher BMI. Previous epidemiology studies all linked saturated fat intake to poorer cognitive function over time. The main difference in this study is that these health care professionals had much lower total trans fat intakes than the average American. Trans fats have been previously associated with poorer cognitive function in other epidemiological studies, and trans fat consumption tracks with saturated fat consumption.

The paper is a little too brief and too heavy on statistical mumbo-jumbo to bother much with coming up with any mechanisms. It does recommend a Mediterranean diet at the end, and immediately classifies PUFAs and MUFAs as "good fats" and saturated fats and trans fats as "bad fats" in the discussion.

I think when it comes down to it, we will find that these women who were chowing down on the saturated fats in the 1990s are going to be women who were less likely to take care of their health in other ways. The olive oil fans were also more educated (even then olive oil was starting to be popular) and likely to take the best care of themselves. I'm not surprised to see these correlations. I still can't figure out how saturated fat all on its own can cause cognitive decline, mechanistically. I find it very interesting that the highest saturated fat eaters had lower levels of hypercholesterolemia in this large group, and the paper makes no attempt whatsoever to explain this finding. Hmmmm.

"Nonaffective psychosis" are psychotic disorders not related to major depressive disorder or bipolar disorder (both of which can cause psychotic symptoms during severe episodes). The most common primary nonaffective psychosis will be schizophrenia, though there are a few other rarer disorders, such as delusional disorder.

Lest we forget who the enemy is, it is inflammation. Yes, our immune system, in the context of our modern lifestyle is often like an group of soldiers armed to the teeth with too much to do on one hand (all these modern epidemics of infections) and too little on the other (wherefore art thou, old friends?). Lest we forget, without inflammation, we will die. Our immune system is necessary, just like an army from time to time.

To put the screws on schizophrenia risk, let's say now, with relative surety, that there is no single cause. Schizophrenia isn't even a single disorder, but rather a variety of disorders with similar enough symptoms to be lumped together by that most imperfect of documents, the DSMIV. But, a few things come up over and over when we look at the suspicious characters, and these things all go back to the immune system (inflammation), genetic risk, and those contributions to the pathology of schizophrenia (ultimately brain damage of a particular kind, a neurodegenerative disease).

Risk factors for developing schizophrenia that I've heard over the years:

Family history
Urban
Advanced paternal age (and to a lesser extent, advanced maternal age)
Infections (particularly toxo and herpes)
Birth in the winter months (could be associated with infections or…)
...Low vitamin D at birth
Complications during pregnancy or birthCannabis use, particularly at a young age

So we get the usual hodgepodge of genetic risk (family history) plus environmental stress (particularly severe stressors that occur when the brain is forming) = increased risk of developing the disease(es). Ultimately at a certain stage of development (typically late adolescence for men and about 10 years later for women), brain cells begin to die, signals misfire, and we end up with the typical symptoms.

It makes perfect sense that if we have a sensitivity to something in our diet, inflammation will increase, and that risk for all sorts of autoimmune conditions and other chronic diseases will increase. And, as we already know, there is an association between schizophrenia and celiac disease, and schizophrenia and weird wheat antibodies.

So now, the new paper in the Green Journal. It's one of those cool studies that are only possible in Scandanavian countries where you pay 70% of your income in taxes and the government keeps tab on all your health information from birth to death. In this case, the neonatal blood samples of a whole population of folks were collected (everyone in born Sweden since 1975) and a sample of folks later diagnosed with schizophrenia and matched healthy controls were analyzed. IgG antibodies (immune response) to gliadin (from wheat) and casein (from milk) were measured. Newborns have immature immune systems and do not make IgG antibodies. These antibodies must have been made by the mother and passed through the placenta in the late stages of pregnancy to the baby.

Don't all run out and get expensive IgG tests to see if you are "sensitive" to foods. I've never seen anything compelling to show me these tests were a reliable indicator of allergies. Wheat is so commonly eaten that almost anyone with an inflamed or "leaky" gut will have IgG antibodies floating around… however, in this study, it was the 10% of folks who had the highest IgG signal to gliadin whose offspring had increased risk of schizophrenia. IgG antibodies to casein were not linked to any increased risk. If only the 5% of babies with the very highest levels of IgG antibodies to gliadin were consider, the odds ratio of developing schizophrenia later in life jumps to 2.5. Don't get me wrong, the absolute risk will still be pretty low, but any time an odds ratio jumps to >2 one should prick up one's ears as it is an interesting finding. These findings were not attenuated by adjusting for confounders.

In general, a highly positive IgG test to gliadin means you have a risk of having celiac disease (though it is not one of the standard tests, which are typically measures of types of HLA genes, anti tissue transglutaminiase, and IgA to gliadin). Did the moms with the highest IgG in this study have untreated celiac disease, and thus a fully flowered autoimmune disease with all the inflammation on board, affecting mom as well as fetus? Sure, except full blown untreated maternal celiac disease is typically associated with malnutrition and small birth weight, whereas in this study there was no correlation between high anti-gliadin IgG and low birth weight. In addition, while 90% of folks with celiac will have the HLA-DQA*0501 and DQB*0201 alleles, these alelles are not increased among folks with schziphrenia.

All told, once again we have a link between wheat and schizophrenia, one not explained by celiac disease alone. More unveiling of the connection needs to be done.

Wednesday, May 9, 2012

I hate the impracticality of magical realism. It seems like hubris to swallow the laws of time and physics in poetry but expect a reader to care about the story. And yet sometimes there is a phrase or paragraph of such power, such wisdom, that you feel gut-punched. Your breath is gone. For that reason a book like One Hundred Years of Solitude should be read. Here is how it begins:

Many years later, as he faced the firing squad, Colonel Aureliano Buendia was to remember that distant afternoon when his father took him to discover ice. At that time Macondo was a village of twenty adobe houses, built on the bank of a river of clear water that ran along a bed of polished stones, which were white and enormous, like prehistoric eggs. The world was so recent that many things lacked names, and in order to indicate them it was necessary to point.

In the village (and later dazzling city of mirrors) Macondo, one can seemingly invent the world according to one's own perceptions. It's a dizzying history, fragmented and timeless. Ultimately, hubris and lack of self reflection lead to the downfall of the Buendia family and of Macondo.

This weekend, something terrible happened to Dr. Jack Kruse. No innocent person should be summarily escorted off a cruise ship and dumped at Galveston harbor by Carnival security and the FBI. I wouldn't wish such a thing on anyone. In fact, six months ago I myself was questioned by Homeland Security, and for a while it seemed certain my computer was going to be confiscated by the feds, though the computer and myself were about 2000 miles away when the actual crime took place. I was a bit shaken up; ultimately there was no way I could possibly end up in trouble, facing the accusation of the federal authorities was an awful experience.

Why am I writing about the Low Carb Cruise event? Well, less than 24 hours after it happened, in a series of tweets and emails and blog posts and facebook posts (some of which are noted on Evelyn's blog), I had learned that *my* name was being circulated as a possible "perpetrator," though Evelyn's has been featured far more prominently and a woman from NY (who could only be Evelyn) was mentioned in a local news story by Kruse himself. There was ugly finger-pointing. "Perpetrators" were being threatened with 15-20 years federal prison time, civil suits, and other nastiness.

I did follow the parody twitter feed (whose tweet about explosives and legionnaire's disease and an "epic bio-hack" was apparently and very unfortunately misinterpreted by Carnival security, though it was obviously a reference to Jack's use of dynamite at his Paleo-Fx talk and his alleged self-injection with MRSA). I even retweeted the feed several times. I thought it was funny, and sometimes the quotes referenced me, for example one about how dangerous bananas can be. I had guesses about who the owner of the feed might be, but did not know. Nor do I have any clue who called (or emailed? The reports differ...) Carnival and apparently pointed security in the direction of Jack Kruse. That person is truly malicious.

How could a relatively mild-tempered psychiatrist who was minding her own business on a Sunday without much of a thought about neurosurgeons, cruises, or microbiology suddenly have her friends email her with forwards of alarming and threatening messages?

I opened the door. I went to Free the Animal not too terribly long ago and engaged Richard Nikoley on his own turf. I made it clear in no uncertain terms that I felt that injecting oneself with MRSA prior to surgery was a stupid and unethical thing to do. Nor do I consider such a statement to be that far out on any limb, or to be that controversial. I'm guessing that if you lined up 10 (non-biohacking neurosurgeon) surgeons and asked them about the incident, 10 out of 10 would say they thought the incident was made up or that the perpetrator was off his rocker. Ultimately I felt that rendering my opinion on the subject was the right thing to do, as silence in the blogosphere is too often associated with approval or assent.

Thereafter things got uglier than usual over at Richard's blog. He publically thrashed Melissa McEwen, and I decided I was sick of the whole scene. I thought I would stick to science and forgo any ranting for a while, and I unfollowed FTA on twitter and on this blog, just as I had previously unfollowed Kruse's twitter and facebook feeds.

A rather peaceful few weeks ensued. But I opened the door. And as much as one can seal it and try to block out any cracks of light, sometimes the door will burst open. It's not the worst thing. A psychiatrist should not shy away from aggression. Aggression has to be met. Actions do have consequences, and when something bad or unpleasant happens, the first thing one should do is reflect upon how one might change the situation, or whether one could have done something differently. What a terrible situation, to be so polarizing and to have engaged in such behavior that someone would actively seek to have you removed from a cruise ship and searched and questioned by homeland security, for example. So angry about what happened, which was indeed a terrible thing, no question, that you bring news cameras to your home and proceed to threaten and bluster even random commenters on David Csonka's website (linked above) who vaguely criticize, and list the telephone number on a public blog of the FBI agent who is investigating the case! No thought of how other innocent people might be irresponsibly blamed or troubled, as it seems Jack was irresponsibly treated by the cruise ship security.

…in that flash of lucidity he became aware that he was unable to bear in his soul the crushing weight of so much past…he admired the persistence of the spiderwebs on the dead rose bushes, the perseverance of the rye grass, the patience of the air in the radiant February dawn. And then he saw the child. It was a dry and bloated bag of skin that all the ants in the world were dragging toward their holes along the stone path in the garden…The first of the line is tied to a tree and the last is being eaten by the ants.

Truth sometimes is strange and awful. Self-reflection can be painful, but helps us to grow. If we do not see it in time, the world we thought we had vanishes, a mirage. No matter how loud or threatening or how aggressive we are, ultimately we return to the earth, and we are only the measure of what people remember.

Dr. Kruse will always have his followers, his believers. They will jump with him off the shore and into the icy waters, and pay the fees for what I consider to be very dubious writings, and all the best of luck to them.

I prefer more solid and boring ground: eat healthy, exercise, sleep, relax, don't invite too much drama upon oneself... though my morbid curiousity is a definite failing. Another weakness to reflect upon, no doubt. There are many.

They have similar designs. Follow a large group of people without dementia at baseline for a number of years, tracking demographic and dietary information along the way. Track new diagnoses of dementia or test people with basic cognitive screens on a regular basis. In addition, the members of the Washington Heights/Hamilton Heights Columbia Aging Project (WHICAP) had plasma beta amyloid peptide measured. It is thought that blood levels of beta amyloid correlate with brain levels, and other studies have shown that higher beta amyloid in the plasma correlates with the onset of dementia.

In the WHICAP crew, those who had higher intake of omega 3 fatty acids had lower levels of plasma beta amyloid, even after adjusting for confounders. This finding would make biologic sense, as omega 3 fatty acids in lipid rafts help cleave amyloid precursor protein (APP) into harmless bits, whereas arachidonic acid in the same place allows for APP to be made into beta amyloid, the component of those plaques that build up in the brain. However, the dietary sources of omega 3 PUFAs are listed as "salad dressing, fish, poultry, margarine, and nuts," which, excepting the fish, are generally terrific dietary sources of omega 6 PUFA, not omega 3. To get an idea of the confounders, "Participants with higher plasma levels of [beta amyloid] peptide were older and less educated and had lower intakes of omega 3 PUFA, omega 6 PUFA, and MUFA…" and "Participants with higher omega 3 PUFA, higher omega 6 PUFA, or higher MUFA intakes had a higher education, were more likely to be white or black and less likely to be Hispanic."

The researchers tried to adjust for subtype of omega 3 PUFA (bless their hearts, considering they were working from food frequency questionnaires) and "none of the subtypes of omega 3 PUFA was significantly associated with the level of beta amyloid, suggesting that overall intake of omega 3 PUFAs might play a more important role." (Or maybe it all just suggests that people who eat "healthy" in general eat fairly healthy who are also better educated and wealthier have a lower risk of dementia and less inflammation on board, as plasma beta amyloid is linked with inflammation and oxidative stress.)

In rodents models, a bit of omega 3 in the chow can reduce plasma beta amyloid by a whopping 70% in a matter of weeks compared to "low DHA control chow" and plaque burden in the brain is "reduced by 40.3%." In human experiments (only one of which measured plasma beta amyloid and have been small), there hasn't been much benefit to adding omega 3s in folks with dementia, though those with mild cognitve impairment might be helped. I'm guessing that it is difficult for a human to be quite as depleted of omega 3 and topped off with omega 6 as much as those lab rats with their shudder-worthy processed rat chow.

In the Nurses Health Study, blueberries and strawberries take center stage. Nurses who admit to eating buckets of them (chock full of the antioxidant anthocyanidin) had better cognitive scores as the study went forward over the decades. And while according to Walter Willett the confounders are easily accounted for, you may not be surprised to know that the berry eating nurses were wealthier, more likely to exercise, more likely to eat fish, and more likely to eat more calories period.

But, in the interest of some discussion, yes, bioflavinoids are very sexy. In the Nurses Health Study, the riches sources were strawberries and blueberries, but tea, oranges, and apples are also common sources. The anthocyanidins in the berries, in particular, are known to be able to cross the blood brain barrier and work in the hippocampus, a central brain area of learning and memory. Not only are they antioxidants, but might also directly deactivate cellular inflammatory mechanisms.

In short, I concur that fish and berries are good for you. However, these studies were not designed to prove that by any means, but rather to point out some interesting population trends as related to dementia and cognitive decline. Consider them pointed out.

I'm working from a paper today (as always) but it is not the world's greatest paper (1). A small study hardly worth mentioning, but the discussion and conclusions have some interest. So put your mind in an open frame but don't believe too much what you are reading.

Depression. Not just a state of mind, really. Can I tell you how common it is for someone to come in to see me, having just experienced a major loss (job or death in the family) and tell me: "My antidepressant isn't working. I'm really sad."

I don't know why it is we are blessed and cursed with emotions. There's some good explanation about how hominids survived via groupings and attachment and all that. We are left with the baggage, as it were. We love. We hate. We murder, and we grieve. Sometimes if you sit outside and let the humid air in through your nose and watch the leaves flicker in the wind you can forget all that for a moment, and just exist, where dying is tomorrow, or yesterday, and not important. Outside of the moment we are left with hopes, ambitions, failures, and loss.

My 9th grade biology teacher, Mr. Turner (who abandonned the profession to become a forest ranger) said to us once: "Evolution is a fact. Deal with it."

We have a hormonal system to deal with trauma of all kinds. Emotional, physicical, present, past. The lack of differentiation is the problem, frankly. But it is what it is. And folks suffering from major depressive episode frequently have activation of the hypothalamic-pituitary-adrenal axis along with an increase in insulin resistance and increased accumulation of visceral fat. Things go to hell in a handbasket pretty quickly. There are elevations in inflammatory cytokines, not just in the brain, but all over the body.

In the traditional medical model, we add antidepressants to the mix. I know there is no such thing as a serotonin or norepinephrine deficiency but bear with me. Long ago, the tricyclics, which can indeed improve depression symptoms but result in an increase in body weight and possible worsening of diabetes. The newer agents of SSRIs (prozac and the like) are actually associated with an improvement in glycemic control.

Weirdly, the old fashioned antidepressants who cause weight gain and dry mouth are known to decrease cortisol, whereas the new ones with fewer weight gain side effect have no immediate effects on the HPA axis. (The wizened psychiatrists who sit in the front row of grand rounds always bemoan the lack of use of the old fashioned antidepressants in favor of the SSRIs. But no one wants to be fat and dry-mouthed, not to mention the death in overdose so possible with the tricyclics).

Wht could be going on? Cortisol from stress centrally increasing craving for high-caloric, palatable food… and increasing the secretion of resistin, an adipokine that causes decreased insulin sensitivity and an increase in fat storage and diabetes? In rats that is probably true. In humans? Not so clear.

Resistin is typiclly released in rats due to inflammatory and obesigenic influences. But what about adiponectin, the supposedly antiinflammatory and anti-obesity hormone release in humans in response to stress or excess sugar… In humans, adiponectin is higher in women than in men, and are reduced in obesity and insulin resistance.

In the small study in the paper I've linked, free cortisol levels (STRESS) were strongly associated with levles of resisin in depressed patients. In follow up, those who were on medicine and had decreased symptoms also had decreased levels of resistin. There were no changes in hormone levels for those who did not improve on antidepressant treatment. BMI was correlated with resistin also.

What do we learn? Depression = increased cortisol secretion = increased resisitin = increased obesity. Direct or indirect mechanisms may be unknown. In mice, increased resistin increases fasting glucose in insulin resistance. This may be true in depressed humans and may explain the link between depression and diabetes. We don't know for sure.

Adiponectin concentrations didn't change during the six weeks of measurements of these depressed patients on or off antidepressants. Only resistin measurements were statistically significant.

The endocrine system is always a bit of an investment in reading, and it doesn't always deliver. That's why we read the Hunger Games Trilogy instead of books about the thyroid. I get it. Peeta v. Gale is more interesting than resistin and adiponectin. That's not hard to understand. We're human, after all. We love, we hate. We let go, we give in.

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.